Biodegradable polymers are useful in a variety of applications, for example, in controlled drug delivery, tissue engineering and medical devices. Advanced biomedical applications require biomaterials to not only provide necessary structural/mechanical support and biodegradability over an appropriate time frame, but also to possess defined chemical and biochemical properties to positively interact with the living system. Biocompatiable and biodegradable polymers that share core structural features while exhibiting incremental variations in chemical functionalities and physical properties are valuable for screening optimal drug delivery vehicles and tissue engineering scaffolds. (Hook, et al. Biomaterials 2010, 31, 187; Hubbell, Nat. Biotechnol. 2004, 22, 828.)
Macromolecular architectures and compositions with a range of mechanical properties and degradation profiles have been reported. (Nair, et al. Prog. Polym. Sci. 2007, 32, 762; Sodergard, et al. Prog. Polym. Sci. 2002, 27, 1123.) For example, aliphatic polycarbonates have attracted increasing interest due to their non-acidic degradation products and potential to introduce properties complementary to those obtainable by other degradable polymers. (Pego, et al. J. Biomater. Sci., Polym. Ed. 2001, 12, 35; Pego, et al. Macromol. Biosci. 2002, 2, 411; Rokicki, Prog. Polym. Sci. 2000, 25, 259; Bat, et al. Biomaterials 2010, 31, 8696; Dankers, et al. Macromolecules 2006, 39, 8763; Zhu, et al. Macromolecules 1991, 24, 1736.) The hydrophobic nature and the lack of side chain functionalities of polycarbonates, however, have limited their biomedical applications. (Zelikin, et al. Biomacromolecules 2006, 7, 3239.) Indeed, such limitations are shared by synthetic biodegradable polymers in general, including polyesters, polyanhydrides, and polyorthoesters. (Vert, Biomacromolecules 2005, 6, 538; Rasal, et al. Prog. Polym. Sci. 2010, 35, 338; Kumar, et al. Adv. Drug Delivery Rev. 2002, 54, 889.)
Current methods for imparting functionalities and improving the hydrophilicity of biodegradable polymers include post-polymerization surface irradiation grafting, post-polymerization end-group modification, polymerization initiated by hydrophilic/functional polymer precursors, and (co)polymerization of functional monomers. (Edlund, et al. J. Am. Chem. Soc. 2005, 127, 8865; Suriano, et al. J. Polym. Sci., Part A: Polym. Chem. 2010, 48, 3271; He, et al. Biomacromolecules 2006, 7, 252; Zhang, et al. J. Controlled Release 2006, 112, 57; Gautier, et al. J. Biomater. Sci., Polym. Ed. 2003, 14, 63; Lu, et al. Macromolecules 2010, 43, 4943; Trollsas, et al. Macromolecules 2000, 33, 4619; Jiang, et al. Abstr. Papers Am. Chem. Soc. 2005, 230, U4073; Gerhardt, et al. Biomacromolecules 2006, 7, 1735; Hu, et al. Biomacromolecules 2008, 9, 553; Pratt, et al. Chem. Commun. 2008, 114; Hu, et al. J. Polym. Sci., Part A: Polym. Chem. 2008, 46, 7022; Hu, et al. J. Polym. Sci., Part A: Polym. Chem. 2007, 45, 5518; Xie, et al. J. Polym. Sci., Part A: Polym. Chem. 2007, 45, 1737; Lou, et al. Macromol. Rapid Commun. 2003, 24, 161; Detrembleur, et al. Macromolecules 2000, 33, 14; Rieger, et al. Macromolecules 2004, 37, 9738; Yin, et al. Macromolecules 1999, 32, 7711.)
(Co)Polymerization of functional monomers provides a straightforward way to introduce functionalities and hydrophilicity with better-controlled polymer compositions and structures provided that suitable monomers could be designed. (Trollsas, et al. Macromolecules 2000, 33, 4619; Gerhardt, et al. Biomacromolecules 2006, 7, 1735.) However, due to the incompatibility of most reactive groups (e.g. hydroxyls, amines, carboxyls, and thiols) with the polymerization conditions, cumbersome protection and post-polymerization deprotection steps involving heavy metal catalysts and lowering overall yields are often required. (Trollsas, et al. Macromolecules 2000, 33, 4619; Hu, et al. Biomacromolecules 2008, 9, 553; Vandenberg, et al. Macromolecules 1999, 32, 3613; Zhang, et al. Macromolecules 2009, 42, 1010; Noga, et al. Biomacromolecules 2008, 9, 2056; Hu, et al. J. Polym. Sci., Part A: Polym. Chem. 2008, 46, 7022; Sanda, et al. Macromolecules 2001, 34, 1564; Kimura, et al. Macromolecules 1988, 21, 3338; Al-Azemi, et al. Macromolecules 1999, 32, 6536; Pounder, et al. Biomacromolecules 2010, 11, 1930.) The degradable nature of the backbone of these polymers also imposes additional challenges to the preparation of well-defined functional derivatives.
Although several monomers with “clickable” functionalities including alkyne- and (methyl)acrylate-containing lactones or carbonates have been reported, a pressing need exists for monomers functionalized with reactive groups orthogonal to polymerization conditions that enable facile post-polymerization functionalization without tedious protection/deprotection. (Parrish, et al. J Am. Chem. Soc. 2005, 127, 7404; Han, et al. Macromol. Biosci. 2008, 8, 638; Jiang, et al. Macromolecules 2008, 41, 1937; Darcos, et al. Polymer Chemistry 2010, 1, 280; van der Ende, et al. Macromolecules 2010, 43, 5665; Chen, et al. Macromolecules 2010, 43, 201; Iha, et al. Chem. Rev. 2009, 109, 5620; Sumerlin, et al. Macromolecules 2010, 43, 1.)
Biocompatible hydrogels are important materials in biomedical research and pharmaceutical products. (Jen, et al. Biotechnol. Bioeng. 1996, 50, 357; Wang, et al. Adv. Drug Delivery Rev. 2010, 62, 699; Gkioni, et al. Tissue Eng. Part B-Rev 2010, 16, 577; Hynd, et al. Biomater. Sci., Polym. Ed. 2007, 18, 1223; Ifkovits, et al. Tissue Eng. 2007, 13, 2369; Khetan, et al. Soft Matter 2011, 7, 830; Kim, et al. Tissue Engineering and Regenerative Medicine 2011, 8, 117; Lee, et al. Chem. Rev. 2001, 101, 1869.) Biocompatible hydrogels have been used as protein microchips, drug and gene delivery carriers, ophthalmic prostheses, and scaffolds for encapsulating cells to facilitate either the investigation of cell-extracellular matrix interactions or tissue regenerations. (Bertone, et al. FEBS J. 2005, 272, 5400; Hoare, et al. Polymer 2008, 49, 1993; Alvarez-Lorenzo, et al. J. Drug Deliv. Sci. Tec. 2010, 20, 237; Drury, et al. Biomaterials 2003, 24, 4337; Tessmar, et al. Adv. Drug Delivery Rev. 2007, 59, 274; Burdick, et al. Adv. Mater. 2011, 23, H41; Minh, et al. Macromolecular Bioscience 2010, 10, 563; Marklein, et al. Adv. Mater. 2010, 22, 175; Anderson, et al. Biomaterials 2011, 32, 3564; Benoit, et al. Nat. Mater. 2008, 7, 816; Haines-Butterick, et al. Proc. Natl. Acad. Sci. U.S.A 2007, 104, 7791; Chung, et al. Tissue Engineering Part A 2009, 15, 243; Annabi, et al. Tissue Eng. Part B-Rev 2010, 16, 371.) Naturally occurring biopolymers such as collagens, fibrin, alginate, agarose, hyaluronan and chondroitin sulfate, as well as synthetic polymers such as poly(ethylene glycol) (PEG), poly(vinyl alcohol) (PVA), poly(N-isopropylacrylamine) (PNIPAAM) have been used for regenerative medicine applications. (Drury, et al. Biomaterials 2003, 24, 4337.)
The chemistry, microstructure and physical properties of hydrogel tissue scaffolds have significant influences on the fate of their resident cells. (Lutolf, et al. Nature 2009, 462, 433; Even-Ram, et al. Cell 2006, 126, 645; Cushing, et al. Science 2007, 316, 1133.) Synthetic hydrogels present unique advantages over naturally occurring hydrogels due to the broader tunability of the properties of the former. (Kloxin, et al. Science 2009, 324, 59; Lee, et al. Biomaterials 2006, 27, 5268; Luo, et al. Nature Materials 2004, 3, 249.) Challenges still exist, however, for the translation of existing synthetic hydrogels for biomedical uses. For instance, the gelling of most physically crosslinked hydrogels requires substantial changes in environmental conditions (e.g., pH, temperature, ionic strength), which can be detrimental to the in situ encapsulated cells. In addition, the integrity of these physically crosslinked cell-gel constructs are difficult to maintain in vivo. On the other hand, the cytotoxicity of crosslinking reagents and initiators used for chemically crosslinked hydrogels can negatively impact the viability and long-term fate of the encapsulated cells. (Mann, et al. Biomaterials 2001, 22, 3045; Rouillard, et al. Tissue Engineering Part C-Methods 2011, 17, 173; Shu, et al. Biomaterials 2003, 24, 3825.)
In general, chemical crosslinking conditions and chemically crosslinked networks deemed cyto-compatible are still limited. (Hennink, et al. Adv. Drug Delivery Rev. 2002, 54, 13.) Among them, PEG-based hydrogels formed by photo-initiated radical polymerization of (meth)acrylated PEG macromers have been the most utilized for the encapsulation and support of tissue-specific differentiation of stem cells. Major limitations associated with photo-crosslinked PEG gels include the intrinsic heterogeneities of the network structures due to the uncontrolled radical polymerization process and the varied degrees of cytotoxicity of the aqueous radical initiators utilized (e.g., I-2959 and VA-086). (Rouillard, et al. Tissue Engineering Part C—Methods 2011, 17, 173.) Alternative in situ crosslinking strategies involving disulfide bond formations or Michael addition reactions between thiols and acryaltes or vinyl sulfones can eliminate the need for radical initiators, but still suffer from the potential interference from the thiol residues widely present within the tissue environment.
Thus, a hydrogel system that can be crosslinked under physiological conditions without external perturbations or cross-reactivities with cellular or tissue environment is highly desired. For tissue regeneration applications, the hydrogels should also ideally possess adequate mechanical properties and exhibit tunable degradation rates potentially matching with those of the tissue integrations.